1. Field of the Invention
This invention relates to topical anti-inflammatory pharmaceutical compositions which are useful for treating diseases of the skin, particularly inflammatory manifestations of corticosteroid-responsive dermatoses. The composition comprises a suitable pharmaceutical solvent and dissolved therein at least two corticosteroid compounds defined hereinafter, each corticosteroid being present at a specific amount relative to the others. Further, the new compositions of this invention provide improvement in the treatment of inflamed condition of the skin. A new method for the preparation of the compositions of this invention is also disclosed.
2. Prior Art
The direct application of drugs to the skin surface has been used since antiquity to treat diseases of the skin. In general, the skin is an effective barrier to the passage of externally applied agents and most chemical substances penetrate intact skin poorly. Since the pharmacological effect of a drug is dependent on achieving a certain threshold concentration in the viable tissues of the skin, effective therapy requires sufficient percutaneous absorption of the drug to achieve the required tissue concentration levels.
The primary barrier to the precutaneous absorption of drugs has been identified as the stratum corneum, the layer of stratified and keratinized dead cells at the skin surface. The ability of chemical agents or drugs to diffuse across the stratum corneum into the deeper tissues is directly related to the physical chemical properties of the drugs. It is known that certain low molecular weight organic solvents such as acetone, chloroform, and dimethyl sulfoxide penetrate the human skin more readily (i.e. at a faster rate) than most drugs, particularly substances of high molecular weight such as corticosteroids. For such compounds, the therapeutic effectiveness is greatly dependent on the rate of diffusion from the topical vehicle (the base) into the skin, i.e. the penetration rate. Increasing the rate of diffusion is an important mechanism for improving therapeutic effectiveness of many topically applied drugs.
The most obvious and commonly used method for increasing the penetration rate of a topically applied drug is to increase its concentration in the vehicle. There are limitations to this approach that bear directly upon the utility of the present invention. For the greatest proportion of skin diseases requiring topical therapy, the skin is the principal barrier to drug absorption and drug absorption proceeds by the process of passive diffusion. Thus only the concentration of drug actually in solution in the vehicle directly affects the drug penetration rate. For a given vehicle and drug, increasing the drug concentration appreciably beyond the saturation concentration in the vehicle will have only a marginal effect on the rate of percutaneous absorption. Thus in a suspension, i.e. a drug formulation wherein a substantial majority of the drug is present in the pure, undissolved state, very little, if any, increase in absorption rate will be seen from adding more excess drug so long as the skin acts as the primary barrier to drug absorption.
Marcus et al. [J. Pharm. Sci., 54, 495-6 (1965)] have described improved in vitro release into water for mixtures of two steroids. In their report data are present for two different mixtures: dexamethasone plus prednisolone and dexamethasone plus betamethasone. The systems described by Marcus et al. differ completely from those described in the present invention. In the Marcus et al. article an experimental situation is described where release from the vehicle is the rate-limiting step in diffusion instead of diffusion through the skin barrier -- the case which normally prevails in the precutaneous absorption of drugs. Marcus et al. describe formulations where the drug is present primarily as suspended solid particles instead of the solubilized systems described in this invention. They also state that rlease is independent of the nature of the vehicle whereas in the present invention vehicle composition must be carefully adjusted depending on the nature and total concentration of the steroid mixture employed. The present invention also requires careful selection of compounds used in a specific vehicle and adjustment of the relative amounts of each steroid according to their saturation solubility. Thus, although an increase in the rate of release of suspended drug into water may be seen, a corresponding rate of penetration of the stratum corneum is not seen using suspension systems because the diffusional resistance of the skin may be any where from 1000 of several million times greater than that offered by water or ointment based vehicles. (See for example Scheuplun, R. J., Molecular Structure and Diffusional Processes Across Intact Epidermis, Final Comprehensive Report No. 7, Springfield U.S. Dept. of Commerce, 1966 and Higuchi, W. I., J. Pharm. Sci., Vol 5, pp. 802-4, 1962. )
The limitations inherent in systems where the drug (or drugs) are presented in the form of suspended material in a vehicle has been analyzed by Katz and Poulsen ("Absorption of Drugs Through The Skin" in Experimental Pharmacology Ed. B. B. Brodie, pub. Springer Verlag 1971) and by Poulsen ("Design of Topical Drug Product: Biopharmaceutics" in Drug Design Vol. 4 Ed. E. J. Ariens, pub. Academic Presd, 1974).
It is known that pregnenolone hemiesters and their salts may be applied topically as a mixture for the treatment of alleviating allergic, pruritic and inflammatory skin conditions. See for example U.S. Pat. No. 3,197,367 issued July 27, 1965 to Panzarella. Not only is this class of compounds completely different from the corticosteroids employed in the composition of this invention, but also a greater percentage of the active ingredients is required for therapeutic activity. It is also mentioned in U.S. Pat. No. 3,743,741 issued July 3, 1973 to Laurent et al. that mixtures of two 9-chloro substituted prednisolones may be used as an ointment. No particular advantage of the mixture over either one alone at an equivalent concentration is discussed, however. The compounds of U.S. Pat. No. 3,743,741 are entirely different than the compounds employed in this invention. Mixtures of 1-dehydrocortisone, 1-dehydrocortisol, and the corresponding 9.alpha.-chloro- or fluoro-derivatives are disclosed in U.S. Pat. No. 3,134,718 to Nobile. The compounds of the Nobile patent are entirely different than the compounds useful in the compositions of this invention and the combination of Nobile is not shown to have any particular advantage over a composition having an equivalent concentration of any of the drugs alone. Another mixture of steroids, fluocortolone and fluocortolone caproate, has been marketed by Schering Ag as Ultralan. These compounds and the ratios at which they are employed are entirely different than the mixture of this invention.
I have now discovered that a particular group of corticosteroids when applied as mixtures in a topical vehicle show an increased rate of penetration of the stratum corneum which is greater than any one of the corticosteroids alone at an equivalent concentration. Surprisingly, the total rate of corticosteroid penetration is substantially additive, a result heretofore not shown in the prior art for pharmaceutical solutions. The new composition of this invention, which is in essence a solution, exhibits a greater penetration rate than does a suspension system of similar composition. Thus, not only does the composition of this invention offer the advantage of greater activity, but also because it is in essence a solution of the drug in an acceptable pharmaceutical solvent, the composition is generally a more homogeneous mixture which is not plagued by crystallization problems as suspensions often are. It has also been found that the combination composition of this invention can be adjusted so that the total concentration of the individual drugs used is small enough to reduce the potential for side effects of any of the individual drugs used at a concentration equivalent to the total concentration of each corticosteroid used in the composition of this invention. This results, of course, in a safer drug composition.